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Atropine
Clinical data
Trade namesAtropen, others
Other namesDaturin[1]
AHFS/Drugs.comMonograph
MedlinePlusa682487
License data
Pregnancy
category
  • AU: A
Routes of
administration		By mouth, intravenous, intramuscular, rectal, ophthalmic
Drug classantimuscarinic (anticholinergic)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability25%
Metabolism≥50% hydrolysed to tropine and tropic acid
Onset of actionc. 1 minute[8]
Elimination half-life2 hours
Duration of action30 to 60 min[8]
Excretion15–50% excreted unchanged in urine
Identifiers
  • (RS)-(8-Methyl-8-azabicyclo[3.2.1]oct-3-yl) 3-hydroxy-2-phenylpropanoate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard100.000.096 Edit this at Wikidata
Chemical and physical data
FormulaC17H23NO3
Molar mass289.375 g·mol−1
3D model (JSmol)
  • CN3[C@H]1CC[C@@H]3C[C@@H](C1)OC(=O)C(CO)c2ccccc2
  • InChI=1S/C17H23NO3/c1-18-13-7-8-14(18)10-15(9-13)21-17(20)16(11-19)12-5-3-2-4-6-12/h2-6,13-16,19H,7-11H2,1H3/t13-,14+,15+,16? checkY
  • Key:RKUNBYITZUJHSG-SPUOUPEWSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery.[9] It is typically given intravenously or by injection into a muscle.[9] Eye drops are also available which are used to treat uveitis and early amblyopia.[10][11] The intravenous solution usually begins working within a minute and lasts half an hour to an hour.[8] Large doses may be required to treat some poisonings.[9]

Common side effects include dry mouth, abnormally large pupils, urinary retention, constipation, and a fast heart rate.[9] It should generally not be used in people with closed-angle glaucoma.[9] While there is no evidence that its use during pregnancy causes birth defects, this has not been well studied so sound clinical judgment should be used.[12] It is likely safe during breastfeeding.[12] It is an antimuscarinic (a type of anticholinergic) that works by inhibiting the parasympathetic nervous system.[9]

Atropine occurs naturally in a number of plants of the nightshade family, including deadly nightshade (Atropa belladonna), jimsonweed (Datura stramonium), mandrake (Mandragora officinarum)[13] and angel's trumpet (Brugmansia).[14] Atropine was first isolated in 1833.[15] It is on the World Health Organization's List of Essential Medicines.[16] It is available as a generic medication.[9][17][18]

Medical uses

[edit]
An ampoule containing atropine injection 0.5mg/1mL

Eyes

[edit]

Topical atropine is used as a cycloplegic, to temporarily paralyze the accommodation reflex, and as a mydriatic, to dilate the pupils.[19] Atropine degrades slowly, typically wearing off in 7 to 14 days, so it is generally used as a therapeutic mydriatic, whereas tropicamide (a shorter-acting cholinergic antagonist) or phenylephrine (an α-adrenergic agonist) is preferred as an aid to ophthalmic examination.[19]

In refractive and accommodative amblyopia, when occlusion is not appropriate sometimes atropine is given to induce blur in the good eye.[20] Evidence suggests that atropine penalization is just as effective as occlusion in improving visual acuity.[21][22]

Antimuscarinic topical medication is effective in slowing myopia progression in children; accommodation difficulties and papillae and follicles are possible side effects.[23] All doses of atropine appear similarly effective, while higher doses have greater side effects.[24] The lower dose of 0.01% is thus generally recommended due to fewer side effects and potential less rebound worsening when the atropine is stopped.[24][25]

Heart

[edit]

Injections of atropine are used in the treatment of symptomatic or unstable bradycardia.

Atropine was previously included in international resuscitation guidelines for use in cardiac arrest associated with asystole and PEA but was removed from these guidelines in 2010 due to a lack of evidence for its effectiveness.[26] For symptomatic bradycardia, the usual dosage is 0.5 to 1 mg IV push; this may be repeated every 3 to 5 minutes, up to a total dose of 3 mg (maximum 0.04 mg/kg).[27]

Atropine is also useful in treating second-degree heart block Mobitz type 1 (Wenckebach block), and also third-degree heart block with a high Purkinje or AV-nodal escape rhythm. It is usually not effective in second-degree heart block Mobitz type 2, and in third-degree heart block with a low Purkinje or ventricular escape rhythm.[citation needed]

Atropine has also been used to prevent a low heart rate during intubation of children; however, the evidence does not support this use.[28]

Secretions

[edit]

Atropine's actions on the parasympathetic nervous system inhibit salivary and mucous glands. The drug may also inhibit sweating via the sympathetic nervous system. This can be useful in treating hyperhidrosis, and can prevent the death rattle of dying patients. Even though atropine has not been officially indicated for either of these purposes by the FDA, it has been used by physicians for these purposes.[29]

Poisonings

[edit]

Atropine acts as an antagonist for organophosphate poisoning by blocking the action of acetylcholine at muscarinic receptors caused by organophosphate insecticides and nerve agents, such as tabun (GA), sarin (GB), soman (GD), and VX. Troops who are likely to be attacked with chemical weapons often carry autoinjectors with atropine and oxime, for rapid injection into the muscles of the thigh. In a developed case of nerve gas poisoning, maximum atropinization is desirable. Atropine is often used in conjunction with the oxime pralidoxime chloride.

Some of the nerve agents attack and destroy acetylcholinesterase by phosphorylation, so the action of acetylcholine becomes excessive and prolonged. Pralidoxime (2-PAM) can be effective against organophosphate poisoning because it can re-cleave this phosphorylation. Atropine can be used to reduce the effect of the poisoning by blocking muscarinic acetylcholine receptors, which would otherwise be overstimulated, by excessive acetylcholine accumulation.

Atropine or diphenhydramine can be used to treat muscarine intoxication.[medical citation needed]

Atropine was added to cafeteria salt shakers in an attempt to poison the staff of Radio Free Europe during the Cold War.[30][31]

Irinotecan-induced diarrhea

[edit]

Atropine has been observed to prevent or treat irinotecan induced acute diarrhea.[32]

Side effects

[edit]

Adverse reactions to atropine include ventricular fibrillation, supraventricular or ventricular tachycardia, dizziness, nausea, blurred vision, loss of balance, dilated pupils, photophobia, dry mouth and potentially extreme confusion, deliriant hallucinations, and excitation especially among the elderly. These latter effects are because atropine can cross the blood–brain barrier. Because of the hallucinogenic properties, some have used the drug recreationally, though this is potentially dangerous and often unpleasant.[medical citation needed]

In overdoses, atropine is poisonous.[medical citation needed] Atropine is sometimes added to potentially addictive drugs, particularly antidiarrhea opioid drugs such as diphenoxylate or difenoxin, wherein the secretion-reducing effects of the atropine can also aid the antidiarrhea effects.[medical citation needed][33]

Although atropine treats bradycardia (slow heart rate) in emergency settings, it can cause paradoxical heart rate slowing when given at very low doses (less than 0.5 mg),[34] presumably as a result of central action in the CNS.[35] One proposed mechanism for atropine's paradoxical bradycardia effect at low doses involves blockade of inhibitory presynaptic muscarinic autoreceptors, thereby blocking a system that inhibits the parasympathetic response.[36]

Atropine is incapacitating at doses of 10 to 20 mg per person. Its LD50 is estimated to be 453 mg per person (by mouth) with a probit slope of 1.8.[37] The antidote to atropine is physostigmine or pilocarpine.[medical citation needed]

A common mnemonic used to describe the physiologic manifestations of atropine overdose is: "hot as a hare, blind as a bat, dry as a bone, red as a beet, and mad as a hatter".[38] These associations reflect the specific changes of warm, dry skin from decreased sweating, blurry vision, decreased lacrimation, vasodilation, and central nervous system effects on muscarinic receptors, type 4 and 5. This set of symptoms is known as anticholinergic toxidrome, and may also be caused by other drugs with anticholinergic effects, such as hyoscine hydrobromide (scopolamine), diphenhydramine, phenothiazine antipsychotics and benztropine.[39]

Contraindications

[edit]

It is generally contraindicated in people with glaucoma, pyloric stenosis, or prostatic hypertrophy, except in doses ordinarily used for preanesthesia.[4]

Chemistry

[edit]

Atropine, a tropane alkaloid, is an enantiomeric mixture of d-hyoscyamine and l-hyoscyamine,[40] with most of its physiological effects due to l-hyoscyamine, the 3(S)-endo isomer of atropine. Its pharmacological effects are due to binding to muscarinic acetylcholine receptors. It is an antimuscarinic agent. Significant levels are achieved in the CNS within 30 minutes to 1 hour and disappear rapidly from the blood with a half-life of 2 hours. About 60% is excreted unchanged in the urine, and most of the rest appears in the urine as hydrolysis and conjugation products. Noratropine (24%), atropine-N-oxide (15%), tropine (2%), and tropic acid (3%) appear to be the major metabolites, while 50% of the administered dose is excreted as apparently unchanged atropine. No conjugates were detectable. Evidence that atropine is present as (+)-hyoscyamine was found, suggesting that stereoselective metabolism of atropine probably occurs.[41] Effects on the iris and ciliary muscle may persist for longer than 72 hours.

The most common atropine compound used in medicine is atropine sulfate (monohydrate) (C
17H
23NO
3)2·H2SO4·H2O, the full chemical name is 1αH,5αH-tropan-3-α-ol (±)-tropate(ester), sulfate monohydrate.

Pharmacology

[edit]

In general, atropine counters the "rest and digest" activity of glands regulated by the parasympathetic nervous system, producing clinical effects such as increased heart rate and delayed gastric emptying. This occurs because atropine is a competitive, reversible antagonist of the muscarinic acetylcholine receptors (acetylcholine being the main neurotransmitter used by the parasympathetic nervous system).

Atropine is a competitive antagonist of the muscarinic acetylcholine receptor types M1, M2, M3, M4 and M5.[42] It is classified as an anticholinergic drug (parasympatholytic).

In cardiac uses, it works as a nonselective muscarinic acetylcholinergic antagonist, increasing firing of the sinoatrial node (SA) and conduction through the atrioventricular node (AV) of the heart, opposes the actions of the vagus nerve, blocks acetylcholine receptor sites, and decreases bronchial secretions.

In the eye, atropine induces mydriasis by blocking the contraction of the circular pupillary sphincter muscle, which is normally stimulated by acetylcholine release, thereby allowing the radial iris dilator muscle to contract and dilate the pupil. Atropine induces cycloplegia by paralyzing the ciliary muscles, whose action inhibits accommodation to allow accurate refraction in children, helps to relieve pain associated with iridocyclitis, and treats ciliary block (malignant) glaucoma.

The vagus (parasympathetic) nerves that innervate the heart release acetylcholine (ACh) as their primary neurotransmitter. ACh binds to muscarinic receptors (M2) that are found principally on cells comprising the sinoatrial (SA) and atrioventricular (AV) nodes. Muscarinic receptors are coupled to the Gi subunit; therefore, vagal activation decreases cAMP. Gi-protein activation also leads to the activation of KACh channels that increase potassium efflux and hyperpolarizes the cells.

Increases in vagal activities to the SA node decrease the firing rate of the pacemaker cells by decreasing the slope of the pacemaker potential (phase 4 of the action potential); this decreases heart rate (negative chronotropy). The change in phase 4 slope results from alterations in potassium and calcium currents, as well as the slow-inward sodium current that is thought to be responsible for the pacemaker current (If). By hyperpolarizing the cells, vagal activation increases the cell's threshold for firing, which contributes to the reduction in the firing rate. Similar electrophysiological effects also occur at the AV node; however, in this tissue, these changes are manifested as a reduction in impulse conduction velocity through the AV node (negative dromotropy). In the resting state, there is a large degree of vagal tone in the heart, which is responsible for low resting heart rates.

There is also some vagal innervation of the atrial muscle, and to a much lesser extent, the ventricular muscle. Vagus activation, therefore, results in modest reductions in atrial contractility (inotropy) and even smaller decreases in ventricular contractility.

Muscarinic receptor antagonists bind to muscarinic receptors thereby preventing ACh from binding to and activating the receptor. By blocking the actions of ACh, muscarinic receptor antagonists very effectively block the effects of vagal nerve activity on the heart. By doing so, they increase heart rate and conduction velocity.

History

[edit]
Atropa belladonna

The name atropine was coined in the 19th century, when pure extracts from the belladonna plant Atropa belladonna were first made.[43] The medicinal use of preparations from plants in the nightshade family is much older however. Mandragora (mandrake) was described by Theophrastus in the fourth century BC for the treatment of wounds, gout, and sleeplessness, and as a love potion. By the first century AD Dioscorides recognized wine of mandrake as an anaesthetic for treatment of pain or sleeplessness, to be given before surgery or cautery.[38] The use of nightshade preparations for anesthesia, often in combination with opium, persisted throughout the Roman and Islamic Empires and continued in Europe until superseded in the 19th century by modern anesthetics.[citation needed]

Atropine-rich extracts from the Egyptian henbane plant (another nightshade) were used by Cleopatra in the last century B.C. to dilate the pupils of her eyes, in the hope that she would appear more alluring[citation needed]. Likewise, it is widely claimed that in the Renaissance, women used the juice of the berries of the nightshade Atropa belladonna to enlarge their pupils for cosmetic reasons. However, primary records of this practice are not known, and the claim may have originated much later by conflating records of actual cosmetic use (for complexion) with the mydriastic properties of atropine. A source from the late 19th century[44] claims that the practice was also current in Paris.

The pharmacological study of belladonna extracts was begun by the German chemist Friedlieb Ferdinand Runge (1795–1867). In 1831, the German pharmacist Heinrich F. G. Mein (1799-1864)[45] succeeded in preparing a pure crystalline form of the active substance, which was named atropine.[46][47] The substance was first synthesized by German chemist Richard Willstätter in 1901.[48]

Natural sources

[edit]

Atropine is found in many members of the family Solanaceae. The most commonly found sources are Atropa belladonna (the deadly nightshade), Datura innoxia, D. wrightii, D. metel, and D. stramonium. Other sources include members of the genera Brugmansia (angel's trumpets) and Hyoscyamus.[40]

Synthesis

[edit]

Atropine can be synthesized by the reaction of tropine with tropic acid in the presence of hydrochloric acid.

Biosynthesis

[edit]

The biosynthesis of atropine starting from l-phenylalanine first undergoes a transamination forming phenylpyruvic acid which is then reduced to phenyl-lactic acid.[49] Coenzyme A then couples phenyl-lactic acid with tropine forming littorine, which then undergoes a radical rearrangement initiated with a P450 enzyme forming hyoscyamine aldehyde.[49] A dehydrogenase then reduces the aldehyde to a primary alcohol making (−)-hyoscyamine, which upon racemization forms atropine.[49]

Society and culture

[edit]

The species name "belladonna" ('beautiful woman' in Italian) comes from the original use of deadly nightshade to dilate the pupils of the eyes for cosmetic effect. Both atropine and the genus name for deadly nightshade derive from Atropos, one of the three Fates who, according to Greek mythology, chose how a person was to die.[38]

[edit]

In March 2025, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Ryjunea, intended for slowing the progression of myopia in children aged 3 to 14 years.[6] The applicant for this medicinal product is Santen Oy.[6] Ryjunea was authorized for medical use in the European Union in June 2025.[6][7]

In March 2025, the CHMP recommended the refusal of a pediatric use marketing authorization for Atropine sulfate FGK, a medicine intended for the treatment of myopia (short-sightedness) in children aged 6 to 10 years of age.[50] In June 2025, FGK Representative Service requested a re-examination by the CHMP.[50]

References

[edit]
[edit]
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Atropine

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Atropine is a tropane alkaloid and competitive antagonist of muscarinic acetylcholine receptors, derived primarily from plants in the Solanaceae family such as Atropa belladonna (deadly nightshade), Datura stramonium (jimsonweed), and Hyoscyamus niger (henbane).[1] As an anticholinergic agent, it inhibits parasympathetic nervous system activity by blocking the action of acetylcholine at muscarinic receptors, resulting in effects such as mydriasis (pupil dilation), tachycardia (increased heart rate), reduced glandular secretions, and relaxation of smooth muscles in the gastrointestinal and respiratory tracts.[1] Medically, atropine is widely used to treat symptomatic bradycardia, organophosphate or muscarinic poisoning, and excessive salivation, and it serves as an antidote in cases of nerve agent exposure or insecticide ingestion.[2] The pharmacological profile of atropine is characterized by its rapid onset and relatively short duration of action, with intravenous administration preferred for acute scenarios due to its quick absorption and distribution.[1] It exerts a direct vagolytic effect on the heart, increasing sinoatrial node firing and atrioventricular conduction, which makes it particularly effective in reversing vagally mediated bradycardia or bradyasystole during cardiac arrest protocols.[2] Topically applied as ophthalmic drops, atropine induces cycloplegia (paralysis of accommodation) and mydriasis for eye examinations or treatment of uveitis and amblyopia, while oral or sublingual forms may be used off-label for sialorrhea in conditions like cerebral palsy.[1] Its mechanism involves competitive inhibition at postganglionic muscarinic sites, sparing nicotinic receptors, which distinguishes it from other anticholinergics and limits certain side effects.[1] Historically, atropine has been recognized for its therapeutic potential since ancient times, with extracts from belladonna particularly used in Renaissance Europe for dilating pupils to enhance cosmetic appeal—hence the name "belladonna" meaning "beautiful lady" in Italian.[1][3] In modern clinical practice, the U.S. Food and Drug Administration (FDA) approves atropine sulfate injections for antisialagogue effects, antivagal actions, and as an antidote for cholinergic toxicity, with dosing typically ranging from 0.5 to 1 mg intravenously for adults in non-emergency settings, up to 2-3 mg for poisoning, and a maximum of 3 mg for bradycardia management.[2] Common adverse effects include dry mouth, blurred vision, urinary retention, and constipation, with overdose potentially leading to delirium, hyperthermia, or the anticholinergic toxidrome marked by "hot as a hare, blind as a bat, dry as a bone, red as a beet, mad as a hatter."[1] Despite these risks, atropine's versatility in emergency medicine, ophthalmology, and toxicology underscores its enduring role as a cornerstone therapeutic agent.[1]

Chemistry

Structure

Atropine is a tropane alkaloid characterized by the molecular formula C17H23NO3C_{17}H_{23}NO_3 and a molecular weight of 289.37 g/mol.[4] It consists of a bicyclic tropane ring system esterified with a tropic acid moiety, specifically forming an ester bond between the hydroxyl group at the 3-position of tropine and the carboxylic acid of tropic acid.[5] The tropine component features a bridged piperidine-pyrrolidine structure with nitrogen at position 8 methylated, while tropic acid is 3-hydroxy-2-phenylpropanoic acid, contributing a phenyl-substituted side chain.[4] The molecule possesses specific chiral centers at the C3 position of the tropane ring and the alpha carbon (C2) of the tropic acid.[5] The systematic IUPAC name for atropine is (1R,3S,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 3-hydroxy-2-phenylpropanoate, reflecting the fixed stereochemistry of the tropane scaffold (1R,5S configuration at the bridgeheads and 3S at the ester attachment).[5] However, the chiral center in the tropic acid renders atropine a racemic mixture. Atropine exists as the racemate dl-hyoscyamine, comprising equimolar amounts of the pharmacologically active (–)-hyoscyamine (l-hyoscyamine) and the inactive (+)-hyoscyamine (d-hyoscyamine).[4] The (–)-hyoscyamine enantiomer features the (S) configuration at the tropic acid chiral center, which is responsible for its biological activity, whereas the racemization at this site produces the optically inactive atropine used clinically.[5] This structural arrangement underpins its anticholinergic properties by mimicking acetylcholine at muscarinic receptors.[4]

Properties

Atropine appears as a white crystalline powder that is odorless and has a bitter taste.[4] It melts at 114–116 °C and sublimes under high vacuum at 93–110 °C.[6] The compound exhibits limited solubility in water, with approximately 1 g dissolving in 455 mL at room temperature and in 90 mL at 80 °C, while it is freely soluble in alcohol (1 g in about 2 mL ethanol) and chloroform (1 g in 1 mL), but insoluble in ether.[7] These solubility characteristics arise from the presence of polar groups such as the ester and tertiary amine in its structure.[4] Chemically, atropine is stable under neutral and acidic conditions but undergoes hydrolysis in strong alkaline environments, breaking down into tropine and tropic acid. Atropine, as a racemic mixture, is optically inactive, whereas the pharmacologically active (-)-hyoscyamine enantiomer has a specific rotation of [α]_D^{20} ≈ -21° in ethanol.[4] The pKa of the tropine nitrogen is approximately 9.8.[6] Atropine is light-sensitive and should be stored in airtight, light-resistant containers to maintain stability, preferably below 40 °C.[4] Solutions of atropine remain stable for several days at 4 °C in water, ethanol, or glycerol.[8]

Pharmacology

Pharmacodynamics

Atropine functions as a competitive, reversible antagonist at muscarinic acetylcholine receptors, which are G-protein-coupled receptors divided into five subtypes (M1 through M5).[1] It binds to these receptors with high affinity, preventing the endogenous neurotransmitter acetylcholine from activating them and thereby blocking parasympathetic neurotransmission.[9] Atropine exhibits non-selective antagonism across all muscarinic subtypes, though its prominent cardiac effects are mediated primarily through blockade of the M2 subtype located on sinoatrial and atrioventricular nodal tissues.[10] This muscarinic receptor antagonism is selective for the parasympathetic nervous system and does not significantly affect nicotinic acetylcholine receptors, distinguishing it from agents like curare that target nicotinic sites.[1] By inhibiting parasympathetic tone, atropine leads to a range of physiological effects, including reduced glandular secretions (such as salivation and lacrimation), decreased smooth muscle contractility in the urinary and gastrointestinal tracts (inhibiting urination and defecation), pupil dilation (mydriasis), paralysis of the ciliary muscle (cycloplegia), and increased heart rate (tachycardia) due to unopposed sympathetic activity.[11] These effects counteract the symptoms of cholinergic excess, often summarized by the mnemonic SLUD (salivation, lacrimation, urination, defecation), which are alleviated through atropine's blockade.[12] The dose-response profile of atropine varies by target tissue and receptor density, with low doses (e.g., 0.5–1 mg intravenously) predominantly eliciting tachycardia via cardiac M2 receptor blockade, while higher doses progressively affect salivary glands, bronchial secretions, and ocular muscles.[1] Central nervous system effects, such as restlessness or confusion, emerge at higher doses because atropine, as a tertiary amine, readily crosses the blood-brain barrier to antagonize central M1, M4, and M5 receptors.[9] In contrast, quaternary ammonium analogs like glycopyrrolate exhibit similar peripheral muscarinic antagonism but lack central effects due to poor blood-brain barrier penetration, making them preferable in scenarios where CNS side effects are undesirable.[9]

Pharmacokinetics

Atropine is rapidly absorbed following intravenous (IV) administration, achieving immediate systemic availability, while intramuscular (IM) absorption is also quick with a bioavailability of approximately 50% and peak plasma concentrations reached within 3 to 60 minutes.[5] Oral absorption is well but variably achieved from the gastrointestinal tract, with bioavailability around 50% and peak levels occurring in 1 to 2 hours in adults, though it is slower and less predictable than parenteral routes.[7] Topical ocular application leads to systemic absorption through the conjunctiva and nasolacrimal drainage, with bioavailability estimated at 64% (±29%) and peak concentrations in about 28 minutes.[1] Following absorption, atropine distributes widely throughout the body with an apparent volume of distribution of 1.0 to 1.7 L/kg.[5] It exhibits moderate plasma protein binding of 14% to 44%, which is saturable at higher concentrations.[5] As a tertiary amine, atropine crosses the blood-brain barrier to produce central nervous system effects, though penetration may be limited compared to quaternary anticholinergics.[7] Metabolism of atropine occurs primarily in the liver through enzymatic hydrolysis, yielding metabolites such as tropic acid, tropine, noratropine, and atropine-N-oxide.[1] This process can be inhibited by organophosphate pesticides.[5] Elimination is mainly renal, with 13% to 50% of the dose excreted unchanged in the urine via glomerular filtration and tubular secretion.[1] The plasma half-life is 2 to 4 hours in adults, and clearance ranges from 5.9 to 6.8 mL/min/kg (approximately 0.4 to 0.5 L/min in a 70 kg adult).[5] Renal excretion is pH-dependent; acidic urine enhances ionization and reduces tubular reabsorption, thereby increasing elimination rates.[7] The pharmacokinetics are nonlinear after parenteral doses due to saturable processes.[1] In special populations, the half-life is prolonged in neonates (5 to 10 hours) and the elderly (10 to 30 hours) owing to reduced clearance and larger volume of distribution.[7] No specific dosage adjustments are typically required for hepatic or renal impairment, but caution is advised in these groups.[1]

Medical uses

Ophthalmologic uses

Atropine is widely used in ophthalmology as a mydriatic and cycloplegic agent to induce pupil dilation and temporary paralysis of the ciliary muscle, primarily through its anticholinergic blockade of muscarinic receptors in the eye. This facilitates refraction testing, particularly in children where accommodation is strong, requiring a potent agent like 1% atropine sulfate solution to achieve accurate measurements.[13] Onset of mydriasis occurs within 30–40 minutes, with maximal cycloplegia reached in 60–90 minutes, and effects persisting for 7–14 days, making it suitable for comprehensive examinations but necessitating caution due to prolonged recovery.[14] In uveitis management, atropine relieves ciliary spasm, reducing pain and photophobia associated with inflammation.[15] To prevent synechiae formation in anterior uveitis, atropine maintains pupillary dilation, breaking or avoiding adhesions between the iris and lens that could lead to complications like glaucoma.[16] Typical dosing involves 1–2 drops of 1% solution administered four times daily (qid) to the affected eye, often combined with anti-inflammatory therapy for optimal control.[17] This approach is particularly effective in moderate to severe cases where shorter-acting agents may fail to sustain dilation.[15] A notable recent advancement is the authorization of Ryjunea, a low-dose atropine sulfate formulation at 0.01% (0.1 mg/mL), approved by the European Commission in June 2025 for slowing myopia progression in pediatric patients.[18] Indicated for children aged 3–14 years with myopia between -0.5 and -6.0 diopters and annual progression of at least 0.5 diopters, it offers a targeted intervention with minimal side effects compared to higher concentrations.[19] Research has also examined the short-term effects of 0.01% atropine on choroidal thickness in young myopic adults (mean age approximately 27 years, spherical equivalent refractive error up to -6.00 diopters, including high myopia). In such individuals, short-term use of 0.01% atropine increases subfoveal choroidal thickness by approximately +6 μm when used alone and reduces hyperopic defocus-induced choroidal thinning (from approximately -11 μm with placebo to -4 μm or less). These are short-term findings from experimental studies; long-term data specifically for young adults with high myopia remain limited, with the majority of choroidal thickening evidence derived from pediatric populations.[20] Atropine is administered topically as eye drops or ointment, with drops preferred for precise dosing and ointments for prolonged contact in inflammatory conditions.[21] Unlike shorter-acting mydriatics like tropicamide, which provides cycloplegia lasting 4–6 hours with onset in 15–30 minutes, atropine's extended duration suits applications requiring sustained effects but may require patient counseling on temporary vision blurring.

Cardiovascular uses

Atropine serves as a first-line treatment for symptomatic bradycardia, particularly when caused by increased vagal tone, by competitively antagonizing muscarinic acetylcholine receptors in cardiac tissue, thereby increasing the sinus rate and atrioventricular conduction.[22] The standard dosing regimen involves an initial intravenous bolus of 1 mg, repeated every 3 to 5 minutes as needed, up to a maximum total dose of 3 mg, until the heart rate improves or alternative therapies are required.[23] This approach is recommended by the American Heart Association for acute management in settings such as advanced cardiovascular life support, where it effectively addresses hemodynamically unstable bradydysrhythmias originating at the sinoatrial or atrioventricular node.[23] In cases of organophosphate poisoning presenting with bradycardia as part of a cholinergic crisis, atropine is administered at higher doses to counteract excessive muscarinic stimulation on the heart.[1] Typical initial dosing starts at 2 to 3 mg intravenously, repeated every 20 to 30 minutes and titrated upward—often using a doubling protocol (e.g., 1 mg, then 2 mg, 4 mg)—until control of cardiac symptoms like bradycardia is achieved, potentially requiring up to 20 mg or more in severe cases.[1][24] This higher dosing reflects the need to overcome profound cholinergic excess, focusing on restoring normal heart rate while monitoring for resolution of associated muscarinic effects.[1] Preoperatively, atropine is used to prevent vagally mediated bradycardia during anesthesia induction, particularly in procedures involving succinylcholine or other agents that heighten parasympathetic activity. In pediatric premedication, intramuscular (IM) atropine is commonly dosed at 0.01–0.02 mg/kg (most often 0.02 mg/kg), administered 30–60 minutes prior to induction to reduce secretions and blunt vagal reflexes. For a typical 5-year-old (~18 kg), this equates to approximately 0.18–0.36 mg IM. Some older guidelines recommend a minimum absolute dose of 0.1 mg to avoid potential paradoxical bradycardia at very low doses, but this has been criticized as a myth that risks overdose in infants under 5 kg, with weight-based dosing preferred and supported by studies showing safe use at 0.01–0.02 mg/kg without paradoxical effects. In modern practice, glycopyrrolate (0.004–0.008 mg/kg IM) is often preferred over atropine for premedication due to longer antisialogogue effect, less tachycardia, and no blood-brain barrier crossing. Doses of 0.4 to 0.6 mg administered intramuscularly or subcutaneously 30 to 60 minutes prior to surgery (adult dosing), or 0.01 to 0.02 mg/kg intravenously immediately before induction, effectively mitigate the risk of transient heart rate slowing. This prophylactic application is especially relevant in pediatric patients or those with baseline vagal hypersensitivity, where it stabilizes hemodynamics without routine use in all cases. A key limitation of atropine in cardiovascular applications is the potential for paradoxical bradycardia at low doses below 0.5 mg, attributed to predominant central nervous system muscarinic blockade that enhances vagal outflow, leading to transient slowing of the sinoatrial node discharge.[22][25] To avoid this adverse effect, dosing guidelines emphasize avoiding subtherapeutic amounts and administering boluses rapidly to ensure peripheral cardiac blockade predominates.[22] Additionally, atropine may be less effective or contraindicated in scenarios like post-cardiac transplant patients due to denervated hearts lacking vagal tone.[22]

Reduction of secretions

Atropine is commonly administered as a preoperative antisialagogue to reduce salivary and respiratory secretions, thereby minimizing the risk of aspiration and improving visualization during anesthesia. Typical dosing involves 0.4–0.6 mg given intramuscularly or intravenously 30–60 minutes prior to surgery, which effectively dries the mouth and oropharynx while counteracting vagal effects.[1][26] In respiratory conditions such as chronic obstructive pulmonary disease (COPD) and asthma, atropine can provide bronchodilation through nebulized administration, though this use is now rare due to the availability of more selective anticholinergics like ipratropium. By inhibiting muscarinic receptors, it reduces mucus production in the airways, which may decrease viscosity and facilitate clearance, particularly in acute exacerbations where secretions contribute to obstruction.[27][1] Atropine also plays a role in palliative care for managing excessive salivation (sialorrhea) associated with Parkinson's disease or terminal conditions at end-of-life. Sublingual administration of a 1% ophthalmic solution, typically 1–2 drops (0.5–1 mg) every 4–6 hours, effectively diminishes oral secretions without requiring systemic injection.[28][29] The onset of atropine's antisecretory effects occurs within 30 minutes following intramuscular or sublingual dosing, with a duration of 4–6 hours, allowing for flexible repeat administration as needed. Alternatives such as scopolamine transdermal patches offer similar suppression of secretions with potentially longer-lasting effects, though they may cause more central nervous system side effects.[1][30]

Antidote for poisonings

Atropine serves as a critical antidote in cholinergic toxicities by competitively antagonizing acetylcholine at muscarinic receptors, thereby reversing excessive parasympathetic stimulation.[1] In organophosphate and carbamate poisonings, which inhibit acetylcholinesterase and cause accumulation of acetylcholine, atropine is administered as part of a standard protocol alongside pralidoxime to manage muscarinic symptoms such as bronchorrhea, bradycardia, and hypersalivation.[1] The initial dose is typically 2 mg intravenously (IV), repeated every 20–30 minutes or doubled if no response, titrated to clinical endpoints like drying of skin and mucous membranes, with total daily doses potentially reaching 100 mg or more in severe cases.[1][31] For muscarine-containing mushroom poisonings, which produce SLUD symptoms (salivation, lacrimation, urination, defecation), atropine effectively counters severe muscarinic effects including excessive bronchial secretions and bradycardia.[32] Dosing begins at 0.5–1 mg IV, with repeat doses as needed every 20–30 minutes until symptoms resolve, typically within 6–24 hours.[33][32] In nerve agent exposures, such as to sarin or VX, military protocols employ high-dose atropine regimens to rapidly mitigate life-threatening cholinergic crisis.[34] The MARK I antidote kit delivers 2 mg intramuscularly (IM) via autoinjector, often administered in sequence with pralidoxime, up to three kits initially and additional doses every 5–10 minutes for severe symptoms until breathing improves.[34] Therapy monitoring focuses on endpoints such as resolution of bronchial secretions, eased ventilation, and stabilization of heart rate, rather than pupil dilation, which is unreliable.[31] Overuse risks include anticholinergic effects like tachycardia, delirium, or respiratory compromise, though serious complications are uncommon when titrated properly in toxicity contexts.[31][1]

Other uses

Atropine is employed in the management of irinotecan-induced diarrhea, particularly the acute cholinergic-mediated form occurring within 24 hours of administration, where subcutaneous or intravenous doses of 0.25–1 mg effectively prevent or alleviate symptoms such as loose stools and abdominal cramps.[35] This application leverages atropine's anticholinergic properties to counteract the cholinergic syndrome triggered by irinotecan's inhibition of acetylcholinesterase.[36] As an antispasmodic agent, atropine has been used for gastrointestinal conditions including irritable bowel syndrome (IBS) and biliary colic, though its role has diminished with the advent of more targeted therapies. Oral dosing typically ranges from 0.4 to 0.6 mg every 4–6 hours as needed for spastic conditions of the gastrointestinal tract, providing symptomatic relief by relaxing smooth muscle.[37] In veterinary medicine, atropine serves as a treatment for bradycardia in dogs and cats, administered intravenously at 0.02–0.04 mg/kg to counteract vagal-mediated heart rate reductions.[38] It is also utilized in equine and bovine practice for select cardiovascular stabilizations, though caution is advised due to risks of reduced gastrointestinal motility.[39] Investigational applications of atropine include exploration for motion sickness prevention via transdermal delivery, drawing on its structural similarity to scopolamine, but progress is limited by comparable side effect profiles such as dry mouth and drowsiness.[40]

Adverse effects

Common side effects

Atropine, as an anticholinergic agent, commonly produces side effects through competitive blockade of muscarinic acetylcholine receptors, leading to predictable dose-related reactions at therapeutic levels.[1] The most prevalent adverse effect is dry mouth (xerostomia), which occurs frequently due to reduced salivary secretions and is often the first noticeable symptom in patients receiving systemic atropine.[41] Other components of the anticholinergic syndrome include blurred vision from cycloplegia and mydriasis, photophobia, constipation resulting from decreased gastrointestinal motility, and urinary retention or hesitancy, particularly in individuals with prostatic hypertrophy.[42] These effects are generally mild and transient, resolving as the drug is metabolized, though they can impact patient comfort during treatment.[1] Cardiovascular side effects, such as tachycardia and palpitations, are common, especially following intravenous administration of doses greater than 1 mg, where heart rate may increase by 20-40 beats per minute due to vagolytic action on the sinoatrial node.[41] Central nervous system effects like dizziness, headache, and confusion are reported, with higher incidence in elderly patients owing to age-related reductions in cholinergic reserve and blood-brain barrier permeability.[42][1] For topical ophthalmic applications, prolonged mydriasis and accommodation paralysis can persist for 7-14 days, contributing to blurred near vision and light sensitivity beyond the intended diagnostic or therapeutic duration.[41]

Overdose and toxicity

Atropine overdose results in an exaggeration of its antimuscarinic pharmacodynamic effects, leading to acute anticholinergic toxicity.[1] Symptoms of atropine intoxication are classically remembered by the mnemonic "hot as a hare, blind as a bat, dry as a bone, red as a beet, mad as a hatter," which captures hyperthermia, mydriasis and blurred vision, anhidrosis and dry mucous membranes, flushed skin, and delirium or hallucinations, respectively.[43] Additional manifestations include tachycardia, tremor, ataxia, urinary retention, and gastrointestinal ileus; severe cases may progress to seizures, coma, circulatory collapse, and respiratory failure.[1] Diagnosis is primarily clinical, based on the presence of tachycardia, mydriasis, and other antimuscarinic signs in the context of known or suspected exposure; routine serum atropine levels are not typically used due to their limited availability and lack of correlation with clinical severity.[1] Management is supportive, focusing on airway protection, hydration, and cooling for hyperthermia. Activated charcoal (60–100 g orally) should be administered if ingestion occurred within 1–2 hours and the patient is not comatose or convulsing.[44] For central nervous system effects like delirium or agitation, physostigmine (1–2 mg IV slowly over 5 minutes, not exceeding 1 mg/min, with atropine available to reverse cholinergic excess) can be used as an antidote, with repeat doses as needed up to a total of 2 mg; benzodiazepines such as diazepam are preferred for seizures or severe agitation to avoid respiratory depression.[45][44] In children, 10 mg or less may be fatal orally; the lethal dose in adults is unknown but estimated at greater than 10 mg, though toxicity can occur at lower doses and survival has been reported with much higher ingestions; intravenous administration is better tolerated due to therapeutic use at doses up to 2–3 mg.[46][1]

Contraindications and interactions

Contraindications

Atropine is absolutely contraindicated in patients with narrow-angle or angle-closure glaucoma, as its anticholinergic effects can precipitate an acute increase in intraocular pressure by blocking aqueous humor outflow.[47] It is also contraindicated in obstructive uropathy, such as benign prostatic hyperplasia (BPH), where it may cause urinary retention by relaxing the detrusor muscle and constricting the bladder neck.[12] Additional absolute contraindications include paralytic ileus, as atropine can exacerbate bowel obstruction by inhibiting gastrointestinal motility.[48] Relative contraindications apply in several patient populations where atropine should be used with extreme caution or avoided if possible. In elderly patients, atropine carries a high risk of central anticholinergic toxicity, including delirium and confusion, even at low doses, as recommended for avoidance under the Beers Criteria except in emergencies.[1] Infants and young children are at risk of hyperthermia due to suppressed sweating and fever induction from inhibited thermoregulation, particularly in hot environments.[47] It should be administered cautiously in patients with tachyarrhythmias, as atropine can further elevate heart rate and exacerbate arrhythmias, and in hiatal hernia associated with reflux esophagitis, where reduced lower esophageal sphincter tone may worsen symptoms.[49] Regarding pregnancy, no animal reproduction studies have been conducted with atropine sulfate. It is not known whether atropine sulfate can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Risk Summary: Available data from postmarketing reports and case series with atropine use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Atropine crosses the placenta and may cause fetal tachycardia. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Atropine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.[2] During lactation, atropine is generally avoided due to its excretion in breast milk, which may cause anticholinergic effects in the infant, including tachycardia and dry mouth, though single doses are unlikely to pose significant risk.[1] FDA guidelines recommend monitoring intraocular pressure in patients with risk factors for glaucoma prior to atropine administration and advise against routine use in contraindicated conditions unless clinically necessary, such as in organophosphate poisoning antidotal therapy.[47]

Drug interactions

Atropine, an anticholinergic agent, can exhibit additive effects when co-administered with other drugs possessing anticholinergic properties, leading to enhanced toxicity such as dry mouth, constipation, urinary retention, tachycardia, and central nervous system disturbances including confusion and delirium.[1] For instance, concurrent use with first-generation antihistamines like diphenhydramine or promethazine intensifies these anticholinergic side effects due to overlapping muscarinic receptor blockade.[1] Similarly, tricyclic antidepressants (TCAs) such as amitriptyline, which have significant anticholinergic activity, can potentiate atropine's effects, increasing the risk of severe anticholinergic syndrome when combined.[1] Antipsychotics like perphenazine also contribute to additive anticholinergic burden, potentially exacerbating symptoms like blurred vision and cognitive impairment.[50] Atropine can antagonize the gastrointestinal effects of certain medications by slowing gastric emptying and reducing motility, thereby altering drug absorption.[51] For example, it decreases the absorption rate of mexiletine, an antiarrhythmic, potentially reducing its therapeutic efficacy.[2] Prokinetic agents like metoclopramide, which enhance gastrointestinal motility, may have their effects opposed by atropine, as demonstrated by reduced increases in lower esophageal sphincter pressure and altered antibiotic absorption when co-administered.[52] In contrast, pralidoxime exhibits synergy with atropine in organophosphate poisoning, where pralidoxime reactivates acetylcholinesterase while atropine counters muscarinic symptoms, improving overall outcomes in combination therapy.[53] Atropine undergoes minimal cytochrome P450 (CYP) metabolism and is primarily hydrolyzed by plasma and hepatic esterases, resulting in limited CYP-mediated drug interactions.[1] However, caution is advised with esterase inhibitors such as organophosphates, which can prolong atropine's duration of action by impairing its hydrolysis, though this is contextually relevant in poisoning scenarios.[54] Representative examples of other interactions include increased tachycardia when atropine is combined with beta-agonists like isoproterenol, due to complementary effects on heart rate.[55] Case reports have also documented enhanced delirium and sedation with opioids, attributed to additive central nervous system depression alongside atropine's anticholinergic contributions.[56]

Natural sources and biosynthesis

Plant sources

Atropine, a tropane alkaloid, is primarily derived from several plant species within the Solanaceae family, which are known for producing anticholinergic compounds. The main natural sources include Atropa belladonna (deadly nightshade), Hyoscyamus niger (henbane), and Datura stramonium (jimsonweed), where hyoscyamine (which racemizes to atropine during extraction) occurs alongside other tropane alkaloids. These plants have been historically gathered from wild populations but are now often commercially cultivated to meet pharmaceutical demands.[57][58] In Atropa belladonna, atropine content varies by plant part, with leaves containing approximately 0.2–0.6% total alkaloids (primarily hyoscyamine, which racemizes to atropine), and roots exhibiting higher concentrations up to 0.5% or more. Hyoscyamus niger yields lower levels, typically 0.03–0.3% total alkaloids in leaves and seeds, with atropine forming a significant portion after processing. Datura stramonium provides 0.2–0.45% alkaloids in leaves and about 0.2% in seeds, making it a favored source for extraction due to its relatively high yield and ease of cultivation. These percentages can fluctuate based on environmental factors like soil quality and climate, but they establish the scale of natural abundance in these species.[59][60][61] These plants are distributed across temperate and subtropical regions, with Atropa belladonna native to Europe, North Africa, and western Asia; Hyoscyamus niger widespread in Europe and the Mediterranean; and Datura stramonium originating from Central America but now naturalized globally. Commercial cultivation has shifted production to controlled farms, particularly in India for Datura stramonium—which supplies a substantial portion of the world's tropane alkaloids—and in parts of Europe for Atropa belladonna and Hyoscyamus niger, optimizing yields through selective breeding and agronomic practices. This contrasts with historical reliance on wild harvesting, reducing contamination risks and ensuring consistent alkaloid profiles.[57][62] Extraction of atropine from these plants typically employs acid-base methods to isolate the alkaloids. Plant material, often dried leaves or roots, is macerated and treated with dilute acid (e.g., hydrochloric acid) to form soluble salts, followed by filtration and basification with ammonia or sodium hydroxide to liberate the free bases, which are then partitioned into an organic solvent like chloroform or dichloromethane for purification. Content is highest in leaves for Datura stramonium and Hyoscyamus niger, while roots of Atropa belladonna offer richer extracts, influencing industrial choices based on yield efficiency. This process yields atropine as the racemic form of hyoscyamine, a key precursor in the plant's alkaloid pathway.[63][64][65] Related alkaloids frequently co-occur with atropine, including hyoscyamine—the levorotatory enantiomer that spontaneously racemizes to atropine during extraction—and scopolamine, which shares the tropane core but differs in esterification. These compounds are biosynthesized together in the plants via pathways involving tropane ring formation, contributing to the mixed alkaloid profiles observed in extracts.[57][66]

Biosynthesis

Hyoscyamine, the precursor to atropine via racemization, is biosynthesized in plants primarily through the tropane alkaloid pathway, which originates from the amino acids ornithine and phenylalanine. The pathway commences with ornithine, an amino acid derived from glutamate metabolism, undergoing decarboxylation catalyzed by ornithine decarboxylase (ODC) to yield putrescine, a polyamine precursor essential for tropane alkaloid formation.[67] Putrescine is subsequently N-methylated by putrescine N-methyltransferase (PMT), a rate-limiting enzyme, to produce N-methylputrescine, which cyclizes—likely via spontaneous or enzymatic steps involving the intermediate 1-methyl-Δ¹-pyrrolinium cation—to form tropinone, the central bicyclic intermediate.[57] This cyclization is facilitated by an atypical polyketide synthase (PYKS) that condenses the pyrrolinium with acetoacetyl-CoA to generate a precursor, followed by decarboxylative processing by a cytochrome P450 enzyme such as CYP82MO1.[68] Tropinone is then stereoselectively reduced by tropinone reductase I (TRI, EC 1.1.1.206) to tropine, the tropane alcohol moiety of atropine, while the acid component, tropic acid, is derived from phenylalanine via transamination to phenylpyruvate, reduction to (R)-3-phenyllactate, and a subsequent 1,2-hydride shift rearrangement to yield (S)-tropic acid.[57] [69] Tropine is esterified with (S)-tropic acid through the action of tropine acyltransferase or similar enzymes to form L-hyoscyamine, the pharmacologically active levorotatory form.[57] L-Hyoscyamine undergoes racemization at the chiral α-carbon of the tropoyl ester due to its low configurational stability, particularly under physiological or extraction conditions, resulting in the equimolar mixture of L- and D-hyoscyamine that constitutes atropine.[70] A parallel branch from L-hyoscyamine involves hyoscyamine 6β-hydroxylase (H6H, EC 1.14.11.11), a bifunctional enzyme that hydroxylates the tropane ring to 6β-hydroxyhyoscyamine and then epoxidizes it to scopolamine, though this diverts flux away from atropine accumulation.[57] Genes encoding key enzymes in this pathway, including ODC, PMT, TRI, and H6H, have been cloned from species such as Atropa belladonna and Hyoscyamus niger, enabling metabolic engineering for enhanced production.[67] [57] These genes have been overexpressed in heterologous systems like Escherichia coli, Saccharomyces cerevisiae, and plant hairy root cultures to optimize tropane alkaloid yields, with strategies such as co-expression of PMT and TRI achieving de novo tropine production up to 1.3 mg/L in yeast.[71] Such efforts highlight the potential for biotechnological improvement of atropine biosynthesis beyond native plant hosts in the Solanaceae family.[71]

Synthesis

Chemical synthesis

The first total synthesis of atropine was accomplished by Richard Willstätter in 1901 through a multi-step process beginning with the formation of tropinone from succindialdehyde, followed by its reduction to tropine and subsequent esterification with tropic acid.[72] This landmark achievement involved over 20 steps for tropinone alone, starting from unrelated precursors like cycloheptanone, and yielded atropine in an overall efficiency of less than 1%, necessitating kilograms of starting materials to produce grams of product.[73] Willstätter's route demonstrated the feasibility of constructing the tropane skeleton chemically but highlighted the complexities of alkaloid synthesis at the time.[74] A more efficient approach emerged in 1917 with Robert Robinson's biomimetic synthesis of tropinone, inspired by the natural assembly of tropane alkaloids, using succinaldehyde, methylamine, and acetonedicarboxylic acid in a single-step Mannich-like condensation to form the bicyclic ketone in high yield.[72] Subsequent refinements by Schöpf in 1937 improved the tropinone yield to approximately 90% under buffered aqueous conditions, making it a cornerstone for modern variants of atropine synthesis.[72] From tropinone, reduction to tropine proceeds via catalytic hydrogenation or metal-mediated methods, such as zinc in hydriodic acid, preferentially yielding the endo-alcohol stereoisomer essential for biological activity.[72] The final coupling step involves esterification of tropine with tropic acid, typically achieved through activation of the carboxylic acid as an acid chloride (e.g., tropoyl chloride) followed by nucleophilic substitution, or via direct condensation using coupling agents like dicyclohexylcarbodiimide (DCC) in the presence of a catalyst such as 4-dimethylaminopyridine (DMAP) for milder conditions.[75] Alternatively, the classical Fischer-Speier method heats tropine and tropic acid in hydrochloric acid to drive ester formation, though it requires careful control to avoid side reactions.[72] Tropic acid itself is typically synthesized via the Ivanov reaction of phenylacetic acid with formaldehyde or by base-promoted hydroxymethylation of phenylacetonitrile followed by hydrolysis of the nitrile. For stereoselective production, asymmetric syntheses target the active (-)-hyoscyamine enantiomer using chiral auxiliaries or catalysts in the tropic acid coupling step, achieving high enantiomeric excess through methods like enzymatic resolution or organocatalytic esterification.[76] Atropine, as the racemic form, is then obtained by base-catalyzed racemization of purified (-)-hyoscyamine, often during isolation or purification, resulting in the 1:1 mixture of (R)- and (S)-enantiomers.[77] Historical routes suffered from low overall yields due to inefficient multi-step assemblies and purification losses, but contemporary laboratory methods leverage Robinson's tropinone synthesis combined with optimized reductions and esterifications to improve efficiency, though total synthesis remains less common than semi-synthetic approaches starting from enantiopure hyoscyamine followed by racemization.[72]

Industrial production

The primary method for industrial production of atropine involves extraction from solanaceous plants, particularly Duboisia myoporoides and Duboisia leichhardtii cultivated on large plantations in Queensland, Australia, which supply approximately 70% of the global demand for tropane alkaloids. Hyoscyamine, the naturally occurring levorotatory precursor, is isolated from the dried leaves through solvent extraction processes, typically involving basification with sodium carbonate solution followed by extraction with organic solvents such as benzene or diethyl ether to yield crude alkaloid mixtures rich in hyoscyamine and scopolamine. This plant-based approach leverages the high alkaloid content in Duboisia leaves, ranging from 0.6% to 1.5% dry weight for hyoscyamine equivalents, enabling efficient commercial scaling.[57][78][79] Following extraction, hyoscyamine undergoes racemization to produce atropine, the racemic mixture of (–)-hyoscyamine and (+)-hyoscyamine, which occurs readily under alkaline conditions or during processing and is intentionally facilitated in industrial settings to meet pharmaceutical specifications. This step is critical as only the (–)-isomer is biologically active, but the racemate provides the standard therapeutic form with balanced potency. To enhance purity, especially for high-demand applications, partial chemical synthesis is employed in good manufacturing practice (GMP)-certified facilities, particularly in India and China, where tropic acid and tropinone derivatives are synthesized and coupled to refine the product beyond plant-extracted yields. These synthetic augmentations address variability in natural sources while maintaining cost-effectiveness.[80][81][82] Purification of the crude atropine sulfate is achieved through techniques such as column chromatography to separate impurities and repeated crystallization from solvents like ethanol or water to attain high purity levels. The final product must comply with United States Pharmacopeia (USP) and European Pharmacopoeia (EP) monographs, requiring not less than 98.5% purity on an anhydrous basis and being endotoxin-free (less than 55.6 USP Endotoxin Units per milligram) for injectable formulations. These standards ensure safety and efficacy in medical applications.[83][7] The global supply chain for atropine centers on Australia's annual harvest of around 1,000 tons of Duboisia leaf material, yielding several tons of refined atropine, though production volumes fluctuate due to climatic factors affecting plant yields, such as rainfall variability in subtropical regions, and occasional supply disruptions from agricultural challenges. Major pharmaceutical manufacturers in Asia process this raw material under GMP conditions to distribute the API worldwide, supporting steady demand for emergency and ophthalmic uses.[78][84]

History

Early history

Atropine, an alkaloid derived from plants in the Solanaceae family such as belladonna (Atropa belladonna) and henbane (Hyoscyamus niger), has roots in ancient medicine for its mydriatic and analgesic properties.[85] In Greek and Roman traditions, belladonna extracts were employed to alleviate pain and induce sedation, while also serving as a poison for suicide, notably associated with Cleopatra's use of henbane-derived atropine in the 1st century BCE to dilate pupils for cosmetic enhancement.[86] Similarly, in ancient Ayurvedic practices, datura (Datura stramonium) preparations containing atropine-like alkaloids were used to treat pain, inflammation, asthma, and rheumatism, with evidence of medicinal and ceremonial applications dating back to prehistoric times in the Indian subcontinent.[87] During the medieval period, atropine's hallucinogenic effects led to its incorporation into witchcraft ointments, often made from henbane or belladonna, which induced sensations of flight and delirium when applied transdermally.[3] In Renaissance Italy, women used belladonna eye drops to dilate pupils, earning the plant the name "belladonna" or "beautiful lady" for its aesthetic appeal in enhancing eye appearance.[88] The isolation of atropine marked a pivotal advancement in the early 19th century. German pharmacist Rudolph Brandes first extracted an impure form of the alkaloid from belladonna roots in 1821, initially identifying it as daturine from related plants.[89] In 1831, Heinrich F. G. Mein obtained a pure crystalline form from belladonna, enabling further study.[90] The substance was formally named atropine in 1833 by Philipp Lorenz Geiger and his assistant Otto Hesse, deriving the term from Atropos, the Greek Fate who severed life threads, reflecting its potent toxicity.[91] By the mid-19th century, atropine underwent therapeutic trials for respiratory and muscular conditions. It was administered via inhalation of stramonium or belladonna leaves to relieve spasmodic asthma, with reports of bronchodilation emerging from European medical literature around 1811 and gaining prominence by the 1870s.[92] Early experiments also explored its antispasmodic effects on gastrointestinal and bronchial smooth muscle, establishing foundational uses in pharmacology.[93]

Modern developments

In the early 20th century, atropine sulfate was recognized by the U.S. Food and Drug Administration (FDA) in 1938 under the Federal Food, Drug, and Cosmetic Act for established clinical uses, including ophthalmic applications and bradycardia treatment. Its role as an antidote for organophosphate poisoning and nerve agents developed during and after World War II. Synthesis advancements began with Richard Willstätter's total synthesis of atropine in 1901, followed by Robert Robinson's 1917 one-pot synthesis of tropinone, a key precursor, which improved yield from 17% to over 90% and enabled scalable production during wartime shortages.[72] During World War II, atropine emerged as a critical antidote against nerve agents like sarin and tabun, blocking muscarinic acetylcholine receptors to counteract cholinergic toxicity in military medical protocols.[94] By the mid-20th century, atropine's ophthalmic applications were standardized, with 1% solutions becoming routine for cycloplegia and mydriasis in pediatric and adult eye examinations, supported by clinical studies evaluating dose efficacy and safety from the 1940s onward.[95] Atropine has been included on the World Health Organization's Model List of Essential Medicines since its inception, underscoring its indispensable role in anesthesia, resuscitation, and emergency care globally.[96] However, its non-selective antagonism of muscarinic receptors prompted research into analogs, such as ipratropium and tiotropium, which offer subtype selectivity (primarily M3 over M2) to minimize cardiac and systemic side effects while targeting respiratory or ophthalmic conditions.[97] In the 21st century, low-dose atropine (0.01%–0.05%) has gained prominence for slowing myopia progression in children, with meta-analyses confirming reduced axial elongation and refractive error advancement without significant photophobia or near-vision impairment.[98] This application culminated in regulatory milestones, including the European Medicines Agency's approval of Ryjunea (0.01% atropine sulfate) in June 2025 for pediatric patients aged 3–14 years, demonstrating 30% slower progression over two years in phase 3 trials.[99] Following EMA approval, the UK Medicines and Healthcare products Regulatory Agency authorized Ryjunea on November 7, 2025. However, in October 2025, the U.S. FDA declined approval for SYD-101, citing insufficient data on long-term efficacy.[100][101] Concurrently, atropine's use has declined in certain scenarios, such as symptomatic bradycardia, where alternatives like temporary pacing or glucagon for beta-blocker overdoses are preferred due to atropine's limited efficacy in infranodal blocks and potential for paradoxical effects at low doses.[1]

Society and culture

Legal status

In the United States, atropine is regulated as a prescription-only medication by the Food and Drug Administration (FDA), requiring a valid prescription for all formulations including injections, oral preparations, and ophthalmic solutions.[47] It is not classified as a controlled substance under the Drug Enforcement Administration (DEA) schedules when used alone, though certain combinations, such as diphenoxylate with atropine, are scheduled as Schedule V due to potential for misuse. Ophthalmic atropine, including low-dose preparations for cycloplegia or myopia management, is available only by prescription and often requires compounding by licensed pharmacies. In October 2025, the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter for a New Drug Application of SYD-101 (0.01% atropine sulfate eye drops, also known as Ryjunea) for slowing myopia progression in pediatric patients, citing insufficient evidence of effectiveness, thus maintaining the need for compounded formulations.[101] In the European Union, atropine is authorized as a prescription-only medicine under the European Medicines Agency (EMA) oversight, with all approved formulations requiring a physician's prescription for dispensing.[99] In 2025, the EMA granted marketing authorization for Ryjunea (low-dose atropine sulfate eye drops) specifically for slowing myopia progression in pediatric patients aged 3-14 years, further emphasizing its restricted access.[102] Internationally, atropine is included on the World Health Organization's (WHO) Model List of Essential Medicines as a core item for its role in anesthesia, emergency care, and poisoning treatment, promoting its availability in health systems worldwide while subject to national regulations.[96] In Australia, it is classified as Schedule 4 (prescription-only) by the Therapeutic Goods Administration (TGA), with additional controls due to its presence in plants like Datura species that carry abuse potential.[103] Veterinary formulations of atropine are regulated separately from human medicines; in the United States, they fall under the FDA's Center for Veterinary Medicine and require veterinary oversight, while in the European Union, they comply with Regulation (EU) 2019/6, limiting use to licensed professionals.[70] Import and export of atropine and its plant extracts are subject to pharmaceutical controls, including FDA import alerts for unapproved drugs and EU requirements for veterinary medicinal products, to prevent unregulated trade.[104]

Formulations and availability

Atropine is available in several pharmaceutical formulations tailored to its routes of administration, including injectable solutions for intravenous or intramuscular use, oral tablets, ophthalmic solutions, and nebulized preparations. Injectable forms are commonly supplied at concentrations of 0.5–1 mg/mL in single-dose syringes or vials, such as 0.5 mg/5 mL or 1 mg/10 mL, allowing for rapid delivery in emergency settings like bradycardia treatment or poisoning reversal.[105] Oral tablets are typically dosed at 0.4 mg for premedication or antispasmodic effects, while ophthalmic solutions range from 0.5–1% (e.g., 1% or 10 mg/mL) in dropper bottles for pupil dilation and cycloplegia.[5] Nebulized atropine is prepared by diluting solutions (e.g., 0.025 mg/kg in 2.5 mL normal saline) for inhalation to manage bronchospasm.[26] Brand-name products include AtroPen, an auto-injector delivering 0.5 mg, 1 mg, or 2 mg doses primarily for military or emergency nerve agent exposure, and Isopto Atropine for ophthalmic use at 1% concentration.[5] Generic versions of atropine sulfate are widely available globally, listed on the World Health Organization's Essential Medicines List, and approved in numerous countries including the United States, Canada, and the European Union. However, occasional supply shortages have occurred in the 2020s, such as the 2023 U.S. shortage of injectable forms due to manufacturing issues and the mid-2025 discontinuation of certain Pfizer syringes, prompting reliance on alternative suppliers like Somerset Therapeutics. As of November 2025, shortages of certain injectable presentations persist.[106][107] The cost of atropine varies by form and region but remains affordable, typically ranging from $0.50 to $5 per dose for generic injectables or oral tablets in most markets, though auto-injectors like AtroPen can exceed $20 per unit.[108] Packaging includes glass ampules or plastic syringes for injectables (e.g., 1 mL or 10 mL volumes in bundles of 10), dropper bottles (5–15 mL) for ophthalmic solutions, and multi-dose vials for nebulization.[105] Storage requirements emphasize protection from light and temperature control: injectables and oral forms are stable for 24 months at 20–25°C (68–77°F) with excursions to 15–30°C permitted, while unopened ophthalmic solutions maintain potency for at least 36 months at room temperature.[109][110] Compounded low-dose ophthalmic preparations (e.g., 0.01%) may require refrigeration for extended stability up to 180 days, though room-temperature storage is often sufficient for 90 days if unopened.[111]

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